C O M M U N I C A T I O N S
Table 3. Alkyne Scope in the Rhodium Catalyzed Oxidative Indole
which the two potential metallated aniline regioisomers undergo
subsequent indolization. These observations as well as a more detailed
mechanistic evaluation and a greater evaluation of scope are underway.
Synthesisa,b
Acknowledgment. Dedicated to Prof. Tomislav Rovis (Colo-
rado State University) on the occasion of his 40th birthday. We
thank NSERC, the Research Corporation, the Sloan Foundation,
the ACS (PRF AC), Merck Frosst, Merck Inc., Amgen, Eli Lilly,
Astra Zeneca, and Boehringer Ingelheim for financial support.
D.R.S. thanks NSERC for a postgraduate scholarship (PGS-D), and
K.M.N.B. thanks NSERC for an undergraduate summer research
award.
Supporting Information Available: Detailed experimental proce-
dures, characterization data for all new compounds, and computational
details. This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) A Beilstein search yielded >45 000 results for indoles with biological
activity.
a Conditions: Acetanilide (1 equiv), alkyne (1.1 equiv), [Cp*RhCl2]2
(2.5 mol%), AgSbF6 (10 mol%), Cu(OAc)2 ·H2O (2.1 equiv), t-AmOH
(0.2 M), 120 °C, 1 h. b Isolated yields are reported above. c Minor
isomer 3-n-hexyl-2-methylindole was isolated in 28% yield (see Sup-
porting Information).
(2) Humphrey, G. R.; Kuethe, J. T. Chem. ReV. 2006, 106, 2875.
(3) For reviews on indole synthesis, see: (a) Gribble, G. W. J. Chem. Soc.
Perkin Trans. 1 2000, 1045. (b) Alonso, F.; Beletskaya, I. P.; Yus, M.
Chem. ReV. 2004, 104, 3079. (c) Nakamura, I.; Yamamoto, Y. Chem. ReV.
2004, 104, 2127. (d) Cacchi, S.; Fabrizi, G. Chem. ReV. 2005, 105, 2873.
For recent individual accounts, see: (e) Shen, M.; Leslie, B. E.; Driver,
T. G. Angew. Chem., Int. Ed. 2008, 47, 5056. (f) Takaya, J.; Udagawa, S.;
Kusama, H.; Iwasawa, N. Angew. Chem., Int. Ed. 2008, 47, 4906. (g) Pei,
T.; Chen, C.-Y.; Dormer, P. G.; Davies, I. W. Angew. Chem., Int. Ed. 2008,
47, 4231. (h) Alex, K.; Tillack, A.; Schwarz, N.; Beller, M. Angew. Chem.,
Int. Ed. 2008, 47, 2304.
as in the reaction of 2-nonyne, a 2:1 regioselectivity is observed for
the formation of 3m where the larger n-hexyl substituent is situated at
C2. As observed with 2a, other aryl-alkyl disubstituted alkynes also
react with high regioselectivity (3n, 3o, and 3p). Heterocyclic
substituents, such as a thiophene (3o) and an indole (3p), may also be
present. Important from a potential application perspective, we have
verified that the acetyl moiety is very easily removed under mild
conditions (KOH or K2CO3 in MeOH/DCM at room temperature) to
provide the free N-H indole.15
To probe the reaction mechanism, d5-acetanilide 1a was subjected
to the standard reaction conditions and the reaction was stopped at
low conversion to reveal significant deuterium loss at the ortho-
positions of the unreacted 1a as well as on the product 3a (Scheme
1). In the absence of Rh catalyst, no reaction and no loss in deuterium
(4) For a review, see: (a) Zeni, G.; Larock, R. C. Chem. ReV. 2004, 104, 2285.
For selected individual accounts, see: (b) Tida, H.; Yuasa, Y.; Kibayashi,
C. J. Org. Chem. 1980, 45, 2938. (c) Sakamoto, T.; Nagano, T.; Kondo,
Y.; Yamanaka, H. Synthesis 1990, 215. (d) Larock, R. C.; Yum, E. K.
J. Am. Chem. Soc. 1991, 113, 6689. (e) Koerber-Ple, K.; Massiot, G. Synlett
1994, 759. (f) Chen, C. Y.; Lieberman, D. R.; Larsen, R. D.; Verhoeven,
T. R.; Reider, P. J. J. Org. Chem. 1997, 62, 2676. (g) Larock, R. C.; Yum,
E. K.; Refvik, M. D. J. Org. Chem. 1998, 63, 7652. (h) Yamazaki, K.;
Nakamura, Y.; Kondo, Y. J. Org. Chem. 2003, 68, 6011. (i) Watanabe, T.;
Arai, S.; Nishida, A. Synlett 2004, 907. (j) Nazare, M.; Schneider, C.;
Lindenschmidt, A.; Will, D. W. Angew. Chem., Int. Ed. 2004, 43, 4526.
(k) Jia, Y.; Zhu, J. J. Org. Chem. 2006, 71, 7826. (l) Leogane, O.; Lebel,
H. Angew. Chem., Int. Ed. 2008, 47, 350. (m) Wurtz, S.; Rakshit, S.;
Neumann, J. J.; Droge, T.; Glorius, F. Angew. Chem., Int. Ed. 2008,Early
View.
(5) ortho-Iodoaniline is $1070/mol, whereas aniline is $12/mol.
(6) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagne´, M. R.; Lloyde-Jones,
G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066.
(7) For recent examples in direct arylation, see: (a) Kalyani, D.; Deprez, N. R.;
Desai, L. V.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 7330. (b)
Daugulis, O.; Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046. For
recent examples in oxidative Heck reactions, see: (c) Boele, M. D. K.;
Strijdonck, G. P. F.; de Vries, A. H. M.; Kamer, P. C. J.; de Vries, J. G.;
van Leeuwen, P. W. N. M. J. Am. Chem. Soc. 2002, 124, 1586. (d) Zaitsev,
V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 4156 For recent examples
in oxidative biaryl formation, see: (e) Li, B.-L.; Tian, S.-L.; Fang, Z.; Shi,
Z.-J. Angew. Chem., Int. Ed. 2008, 47, 1115. (f) Brasche, G.; Garcia-
Fortanet, J.; Buchwald, S. L. Org. Lett. 2008, 10, 2207.
Scheme 1. Mechanistic Studies
(8) Only unreacted acetanilide (1a) and trace amounts of a multiple alkyne
insertion product previously observed by Heck appeared in the GCMS
trace. Wu, G.; Rheingold, A. L.; Heck, R. F. Organometallics 1986, 5,
1922.
(9) Aulwurm, U. R.; Melchinger, J. U.; Kisch, H. Organometallics 1995, 14,
3385.
(10) (a) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407. (b) Umeda,
N.; Tsurugi, H.; Satoh, T.; Miura, M. Angew. Chem., Int. Ed. 2008, 47,
4019.
(11) Li, L.; Brennessel, W. W.; Jones, W. D. J. Am. Chem. Soc. 2008, 130,
12414.
(12) For the use of this complex in the cleavage of other stong bonds, see: Taw,
F. L.; Mueller, A. H.; Bergman, R. G.; Brookhart, M. J. Am. Chem. Soc.
2003, 125, 9808.
(13) A similar effect has been observed in rhodium catalyzed carbonylation
reactions. See: Grushin, V. V.; Marshall, W. J.; Thorn, D. L. AdV. Synth.
Catal. 2001, 343, 161.
(14) In the reaction yielding 3a the regioselectivity is >40:1 by GCMS.
(15) All yields for deacetylation were equal to or greater than 90%, and reaction
times were between 15 min to 1 h. Please see Supporting Information for
specific conditions and representative examples.
are observed. This may arise from a fast and reversible arene
metalation/proto(deutero)demetalation step prior to cross-coupling with
the alkyne. Interestingly, when nonsymmetrical aniline 1i (which
undergoes indolization at the more sterically accessible ortho-position)
is allowed to react in d1-tert-amyl alcohol as the solvent and stopped
at early conversions, more deuteration is actually observed at the more
sterically hindered ortho-position (50%) than at the eventual site of
indole formation (21%). This may indicate that the regioselectivity is
controlled not by the site of aniline rhodation but by the ease with
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